Is NR2F2 p.Pro43= (c.129C>G) pathogenic?

NR2F2 p.Pro43= (c.129C>G) is classified Likely benign in NR2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). Ultra-rare (popmax 0.0795%, nfe); Associated with congenital heart defects, multiple types, 4.

What condition is associated with NR2F2 p.Pro43= (c.129C>G)?

NR2F2 p.Pro43= (c.129C>G) is associated with congenital heart defects, multiple types, 4 (ClinVar).

How common is NR2F2 p.Pro43= (c.129C>G) in the general population?

NR2F2 p.Pro43= (c.129C>G) is ultra-rare (popmax 0.0795%, nfe) (gnomAD).

NR2F2 p.Pro43=

c.129C>G · rs551936462 · VCV241369

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0795%, nfe)

Conditions

congenital heart defects, multiple types, 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2	GERP -3.3
Overall
CADD	8.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0795% European (non-Finnish) · 908/1,141,812 alleles

Filtering AF 0.0752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0735%

Overall 0.0634% 973/1,534,484 alleles · ultra-rare exomes 932/1,382,664 · genomes 41/151,820 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0795%	1,258
Remaining individualsnot grpmax-eligible	0.0471%	2,123
Admixed American	0.0396%	2,525
Middle Eastern	0.0182%	5,486
African / African-American	0.0179%	5,592
Ashkenazi Jewishnot grpmax-eligible	0.00711%	14,060
Finnishnot grpmax-eligible	0.00194%	51,488

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NR2F2
Protein: p.Pro43=
Coding: c.129C>G
MANE Select: NM_021005
dbSNP: rs551936462
Type: single nucleotide variant
Location: chr15:96332234 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 1 PDB
Residue 43: the 'disordered' region

Full NR2F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital heart defects, multiple types, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NR2F2 p.Ser341Tyr Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Trp249Ter Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Ala2Ser Uncertain significance ★★ ⚠ same condition
NR2F2 p.Gly180Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Gly361Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.His90Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Pro32Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Thr358Met Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nr2f2-p-pro43 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown